| 1. |
- Agholme, Lotta
(författare)
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The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.
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| 2. |
- Bagheri, Maryam
(författare)
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Neuroprotective Effect of Genistein : Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.
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| 3. |
- Bjartmar, Lisa, 1966-
(författare)
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Pharmacological and Developmental Aspects on Neuronal Plasticity
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.
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| 4. |
- Degerman Gunnarsson, Malin, 1969-
(författare)
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Biomarkers as Monitors of Drug Effect, Diagnostic Tools and Predictors of Deterioration Rate in Alzheimer’s Disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Decreased amyloid-ß42 (Aß42), increased total tau (t-tau) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) reflect histopathological core changes in the most common dementia disorder, Alzheimer’s disease (AD). They discriminate AD from healthy controls and predict conversion to AD with a relatively high accuracy. Memantine, an uncompetitive NMDA-receptor antagonist, is indicated for symptomatic treatment of AD. The first aim of this thesis was to investigate effects of memantine on CSF concentrations of Aβ42, tau and p-tau. Secondly, the aim was to explore the relation between these CSF biomarkers and retention of the amyloid biomarker Pittsburgh compound B using positron emission tomography (PIB PET), regional glucose metabolism measured with 18Fluoro-2-deoxy-d-glucose (FDG) PET and neuropsychological test performance. The third aim was to investigate their possible utility as predictors of future rate of AD dementia deterioration. All patients in the studies were recruited from the Memory Clinic, Uppsala University Hospital. In study I CSF p-tau concentrations in 11 AD patients were reduced after twelve months treatment with memantine, indicating that this compound may affect a key pathological process in AD. Results from study II showed that the concentrations of CSF Aß42 are lower in PIB+ patients than in PIB- patients, and that the PIB retention was stable during 12 months. In study III 10 patients with the diagnoses AD (6 PIB+/4 PIB-) and 8 subjects (1 PIB+/7 PIB-) with frontotemporal dementia were included. PIB+ patients had lower psychomotor speed measured by performance on the Trail Making Test A and impaired visual episodic memory compared to the PIB- patients. The initial clinical diagnoses were changed in 33% of the patients (6/18) during follow-up. Study IV is the first-ever report of an association between high CSF tau and dying in severe dementia. These 196 AD patients were followed up to nine years after baseline lumbar puncture. Moreover, CSF t-tau concentrations above median was associated with an increased risk of rapid cognitive decline (OR 3.31 (95% CI 1.53-7.16), independently of baseline functional stage. Thus, a clear association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease was shown.
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| 5. |
- Domert, Jakob, 1986-
(författare)
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Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system. We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation. As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity. We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer. Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.
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| 6. |
- Dong, Huan-Ji, 1981-
(författare)
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Health Maintenance in Very Old Age : Medical Conditions, Functional Outcome and Nutritional Status
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to provide better understanding of the underlying factors related to health maintenance in very old people, with a focus on medical conditions, functional outcome and nutritional status. Data were gathered from the ELSA 85 project (Elderly in Linköping Screening Assessment). The ELSA 85 project was started in 2007 with a population-based survey of 85-year-old individuals (n = 650) residing in Linköping municipality, Sweden. During the study period from 2007 to 2010, we conducted surveys by postal questionnaire, home visits, geriatric clinic visits, and reviews of electronic medical records as well as the database of health service consumption. A series of cross-sectional analyses were performed on multimorbidity, health service consumption, activities of daily living (ADLs), physical functioning and nutritional status.Of 650 eligible individuals, 496 (78% of those alive) completed the questionnaire (Paper I). Despite the prevalence of multimorbidity (68%) and frequent use of assistive technology for mobility (40%), the majority managed self-care (85%), usual activities (74%) and had high self-rated health (>60/100, visual analogue scale). Factors associated with in-patient care were an increased number of general practitioner visits, more use of assistive technology, community assistance, multimorbidity (≥2 chronic diseases) and/or heart failure and arrhythmia.Cluster analyses (n = 496, Paper II) revealed five clusters: vascular, cardiopulmonary, cardiac (only for men), somatic–mental (only for men), mental disease (only for women), and three other clusters related to ageing (one for men and two for women). Heart failure in men (odds ratio [OR], 2.4; 95% confidence interval [CI], 1–5.7) and women (OR, 3; 95% CI, 1.3–6.9) as a single morbidity explained more variance than morbidity clusters in models of emergency room visits. Men’s cardiac cluster (OR, 1.6; 95% CI, 1–2.7) and women’s cardiopulmonary cluster (OR, 1.7; 95% CI, 1.2–2.4) were significantly associated with hospitalization. The combination of the cardiopulmonary cluster with the men’s cardiac cluster (OR, 1.6; 95% CI, 1–2.4) and one of the women’s ageing clusters (OR, 0.5; 95% CI, 0.3–0.8) showed interaction effects on hospitalization.In Paper III, overweight (body mass index [BMI], 25–29.9 kg/m2) and obese (BMI, ≥30 kg/m2) individuals (n = 333) perceived more difficulty performing instrumental ADL (IADL) and had more comorbidities than their normal weight counterparts (BMI, 18.5–24.9 kg/m2). After controlling for socio-demographic factors, obese but not overweight individuals were more likely to perceive increased difficulty in performing outdoor activities (OR, 2.1; 95% CI, 1.1–4) and cleaning (OR, 2.2; 95% CI, 1.2–4.2) than their normal weight counterparts. Although obesity was also associated with multimorbidity (OR, 3; 95% CI, 1.2–8), the health service cost of each case of multimorbidity (n = 251) was highest in individuals of normal weight and nearly three times as much as in obese individuals (ratio, 2.9; 95% CI, 1.1–8.1).In Paper IV, 88-year-old obese women (n = 83) had greater absolute waist circumference, fat mass (FM) and fat-free mass (FFM), and lower handgrip strength (HS) corrected for FFM and HS-based ratios (HS/weight (Wt), HS/BMI, HS/FFM and HS/FM) than their normal weight and overweight counterparts. After adjusting for physical activity levels and the number of chronic diseases, the HS-based ratios explained more variance in physical functioning in Short Form-36 (R2, 0.52–0.54) than other single anthropometric or body composition parameters (R2, 0.45–0.51). Waist circumference, HS, and two HS-based ratios (HS/Wt and HS/FFM) were also associated with the number of IADL with no difficulty.In conclusion, the ELSA 85 population showed a fairly positive image of healthy perception, good functional ability as well as low use of health care among the majority of participants. Patterns of cardiac and pulmonary conditions were better associated than any single morbidity with hospitalization. Heart failure as a single morbidity was better associated than multimorbidity patterns with emergency room visits. For 85-year-olds, being obese, as opposed to overweight, was associated with self-reported activity limitations and comorbidities. Overweight elderly living in their own homes in this population had similar well-being to those of normal weight. In the cohort of 88-year-olds, obese women had high waist circumference, but their HS was relatively low in relation to their Wt and FFM. These parameters were better than BMI for predicting physical function and independent daily living.
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| 7. |
- Franzon, Kristin
(författare)
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Independent Ageing in Very Old Swedish Men
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Predictors for survival have been investigated thoroughly, but less is known about how to reach high age with preserved physical and cognitive function. These functions are crucial to stay independent in daily life, which is highly valued by the oldest old.This thesis was based on data from the Uppsala Longitudinal Study in Adult Men. In 1970, all men born in 1920-24 and living in Uppsala were invited to the study, and 82% (n=2,322) participated in the first investigation. In this thesis, data are used from the investigations cycles at the ages of 50, 71, 87 and 92 years. Independent ageing was defined as follows: having independency in personal care and the ability to walk outdoors alone, being community-dwelling, having a Mini-Mental State Examination score of 25 points or greater, and having no diagnosed dementia.Thirty-seven percent of the original cohort survived to the age of 85. At a mean age of 87, 74% of the participants were independently aged, while at a mean age of 92 the prevalence of independent ageing was 64%. In Paper I, non-smoking and normal weight at a mean age of 50 were associated with independent ageing at a mean age of 87 years. In Paper II, never smoking, not being obese, and a high adherence to a Mediterranean-like diet at a mean age of 71 were associated with independent ageing at a mean age of 87. In both Papers I and II, high leisure time physical activity was associated with survival, but not with independent ageing. In Paper III, higher gait speed and hand grip strength and a faster chair stand test were cross-sectionally associated with independent ageing at a mean age of 87. Higher gait speed was also longitudinally associated with independent ageing five years. However, muscle mass and sarcopenia were not associated with the outcome. In Paper IV, a history of stroke, osteoarthritis, hip fracture and chronic obstructive pulmonary disease were associated with loss of independent ageing at a mean age of 92.Smoking, weight and diet are all modifiable risk factors associated with independent ageing. If decreased smoking and a normalised weight in the population could diminish stroke, hip fracture, chronic obstructive pulmonary disease and osteoarthritis, the prevalence of independent ageing could rise, even in nonagenarians. Additionally, a Mediterranean-like diet may contribute to both survival and independent ageing.
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| 8. |
- Johansson, Maria, 1967-
(författare)
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Cognitive impairment and its consequences in everyday life
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim was to improve knowledge of the consequences of cognitive dysfunction in everyday life and of instruments to make these assessments. The thesis contains four studies each of different design using different populations.In study I, the relationship between cognitive function, ability to perform activities of daily living and perceived health-related quality of life were investigated in a population of 85-year-old individuals in the community of Linköping (n = 373). The study was part of the Elderly in Linköping Screening Assessment 85 (ELSA 85). Even mild cognitive dysfunction correlated with impaired ability to perform activities of daily living and lower health-related quality of life.In study II, the diagnostic accuracy and clinical utility of Cognistat, a cognitive screening instrument, were evaluated for identifying individuals with cognitive impairment in a primary care population. Cognistat has relatively good diagnostic accuracy with a sensitivity of 0.85, a specificity of 0.79 and a Clinical Utility Index (CUI) of 0.72. The corresponding values were 0.59, 0.91 and 0.53 for the Mini Mental State Examination (MMSE), and 0.26, 0.88 and 0.20 for the Clock Drawing Test (CDT).In study III, the aim was to develop an instrument measuring self-perceived or caregiver reported ability to perform everyday life activities in persons with suspected cognitive impairment or dementia and to perform psychometric testing of this instrument, named the Cognitive Impairment in Daily Life (CID). The CID was found to have good content validity.In study IV, experiences of cognitive impairment, its consequences in everyday life and the need for support in persons with mild cognitive impairment (MCI) or mild dementia and their relatives were explored. Interviews were performed with five people with MCI, eight people with mild dementia and their relatives (n = 13). The main finding was that persons with MCI and dementia experienced cognitive changes that could be burdensome and result in changed activity patterns.In conclusion, the findings support earlier research and show that cognitive dysfunction even at mild stages has an impact on everyday life and reduces perceived quality of life. To improve interventions for persons with cognitive impairment, it is important to assess not only cognitive function but also its consequences in everyday life activities.
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| 9. |
- Ludvigsson, Mikael, 1976-
(författare)
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Subsyndromal depression hos äldre äldre personer
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund: Subsyndromal depression (SSD) eller subklinisk depression är ett vanligt affektivt tillstånd som kan beskrivas som depressivitet under gränsen för vad som kallas syndromal eller egentlig depressiv episod. Förekomsten av SSD har rapporterats vara ungefär 10 % i populationen, eller ungefär 2-3 gånger högre än förekomsten av syndromal depression. SSD jämfört med icke-depression (ND) är associerat med en lägre aktivitetsförmåga (ADL, Activities of Daily Living), lägre kognitiv funktion, lägre subjektiv hälsa, sämre psykiska utfall och en högre dödlighet. Emellertid har flertalet studier om SSD hos äldre gjorts i åldersgruppen yngre äldre (60-80 års ålder), medan få studier har undersökt SSD hos äldre äldre personer (80+ års ålder). Eftersom många aspekter (t ex multisjukdom, skörhet, funktionsförmågor och socialt beroende) generellt förändras mellan yngre äldre och äldre äldre åldrar, så finns det ett behov av ökad kunskap om SSD hos äldre äldre. Syftet med denna avhandling var att beskriva SSD, eller det komplexa området mellan syndromal depression och normalt åldrande, hos äldre äldre personer.Metod: studie 1 baserades på kvalitativa intervjuer (n=27), medan studier 2-4 till stor del baserades på data från en prospektiv observationsstudie av en kohort, ”Elderly in Linköping Screening Assessment” (ELSA85). ELSA85 hade en populationsbaserad design där man följde personer från 85 års ålder i tre uppföljande mätvågor. Depressivitet mättes med 15- frågeversionen av Geriatric Depression Scale (GDS-15), som också användes för att definiera SSD i studierna.Resultat: Analysen av de kvalitativa intervjuerna (studie 1) resulterade i fyra teman (livet går ned och kroppen sviktar, att klara sig själv, att hänga med, och att ta en dag i taget), vilka tillsammans gav en helhetsbild av SSD i de högsta åldrarna. I en jämförelse mellan SSD, ND och syndromal depression, så skiljde sig SSD kvalitativt från syndromal depression, men däremot inte tydligt från ND. En tvärsnittsanalys av data från baslinjen av studien (studie 2) identifierade associerade faktorer till SSD bland äldre äldre personer, och enligt analysen med multipel logistisk respektive linjär regression så var det fyra domäner (sociodemografiska faktorer, sviktande fysisk funktion, neuropsykiatriska faktorer och existentiella faktorer) som var signifikant associerade med SSD.I en fem års longitudinell uppföljning (studie 3) visades att direkta hälso- och sjukvårdskostnader per överlevnadsmånad och person var förhöjd hos personer med SSD jämfört med ND med ett storleksförhållande 1.45 (€634 vs €436), vilket var en signifikant skillnad även när man kontrollerade för somatisk multisjukdom. I en åtta års longitudinell uppföljning visades att dödligheten var förhöjd (dödsintensitet eller Hazard ratio (HR))=1.33) för personer med SSD jämfört med ND, liksom sjuklighet avseende personlig ADL (P-ADL), instrumentell ADL (IADL), ensamhet, subjektiv hälsa, och depressivitet. Däremot var inte kognitiv snabbhet, exekutiva funktioner eller global kognitiv funktion signifikant försämrade när man hade kontrollerat för relevanta variabler.Slutsatser: SSD hos äldre äldre personer ser olika ut hos olika personer, och personal i hälso- och sjukvården bör vara uppmärksamma på även andra depressiva tecken förutom de klassiska symtomen i diagnosregistren. SSD hos äldre äldre är associerat med förhöjda sjukvårdskostnader, förhöjd sjuklighet och dödlighet. Med tanke på den höga förekomsten av SSD och den demografiska utvecklingen med ökande antal äldre äldre personer i samhället, så indikerar fynden behovet av att utveckla kliniska och samhälleliga strategier för att förebygga SSD och associerade negativa utfall.
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| 10. |
- Ludvigsson, Mikael, 1976-
(författare)
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Subsyndromal Depression in Very Old Persons
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Subsyndromal depression (SSD) or subthreshold depression is a common affective condition that can be described as depressiveness below the threshold of what is called a syndromal or a major depressive episode. The point prevalence for SSD has been reported to be about 10% in the community, or about two or three times higher than the prevalence for syndromal depression. In elderly persons, SSD compared to non-depression (ND) is associated with impaired activities of daily living, lower cognitive function, lower self-perceived health, worse psychiatric outcomes and higher mortality. However, most studies on SSD in elderly persons have been done in the young old age group (age 60-80 years), while few studies have investigated SSD in very old persons (age 80+). As many aspects (e.g. multimorbidity, frailty, functional decline and social dependence) change between the young old and the very old ages, there is a need for more knowledge about SSD in the very old. The overall aim of this doctoral thesis was to describe SSD, or the complex area between syndromal depression and normal aging, in very old persons.Method: Paper 1 was based on qualitative interviews (n=27), while papers 2-4 were based largely on data from a prospective observational cohort study “Elderly in Linköping Screening Assessment” (ELSA85), with a population-based design following the participants from the age of 85 in three waves of follow-up. The 15-item Geriatric Depression Scale (GDS-15) was used for measuring depressiveness and to define SSD in the studies.Results: The analysis of the qualitative interviews (paper 1) resulted in four themes (life curve and the body go down, to manage on one’s own, to keep up with life, and taking one day at a time), giving a comprehensive picture of SSD in very old age. In a comparison among SSD, ND and syndromal depression, SSD differed qualitatively from syndromal depression, but not clearly from ND. A cross-sectional analysis of data from baseline (paper 2) identified factors associated with SSD in very old persons, and according to analyses with multiple logistic and linear regressions, four domains (sociodemographic factors, declining physical functioning, neuropsychiatric factors, and existential factors) were significantly associated with SSD.A five-year longitudinal follow-up (paper 3) showed that direct healthcare costs per month of survival for persons with SSD exceeded those of persons with ND by a ratio of 1.45 (€634 vs €436), a difference that was significant even after controlling for somatic multimorbidity.An eight-year longitudinal follow-up (paper 4) showed that mortality was elevated (hazard ratio=1.33) for persons with SSD compared to ND, as were morbidity regarding basic ADL, IADL, loneliness, self-perceived health and depressiveness, whereas cognitive speed, executive functions and global cognitive function were not significantly impaired when adjusting for covariates.Conclusion: SSD in very old persons has a different presentation in different persons, and healthcare personnel should be attentive to other depressive signs beside the classical ones in the diagnostic classification registries. SSD in the very old is associated with elevated direct healthcare costs, morbidity and mortality. Considering the high prevalence of SSD and the demographic development of increasing numbers of very old people, the findings highlight the need to develop clinical and societal strategies to prevent SSD and associated negative outcomes.
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